Understanding how the survival, differentiation and formation of effector and memory T cells are coordinated during the response to infection is of significant importance to human health. Our studies aim to define the molecular pathways underlying the generation and function of human memory T cells, which provide protective immunity from recurring infections. As the molecular pathways that mediate the induction of long-lived memory T cells during the immune response are deciphered, the strategic design of therapeutic and protective vaccines will be improved.) PUBLIC HEALTH RELEVANCE: T cells provide protection against a wide array of infections by directly eliminating the invading pathogen, coordinating the responses of innate and adaptive cells, and forming long-lived protective immunity, or immunological memory. Integration of the generation, proliferation, survival, and death of T cells ensures that cell numbers are maintained at a constant level and the host is protected in spite of the continual barrage of immunological insults. We have discovered that the transcriptional repressor Zeb2 controls the formation of CD8+ T cell effector and memory subsets during infection, thus regulating the number of cells that provide short-term vs. long-lived protection from subsequent pathogen exposure. We hypothesize that Zeb2 promotes the differentiation of CD8+ T cells to a shorter-lived, effector-memory population during the immune response by repressing expression of genes that are regulated by E protein transcription factors. To gain insight into how Zeb2 influences the immune response and the formation of CD8+ memory cells we propose to: 1) Identify novel roles for Zeb2 in activation, differentiation and effector function of immune cells. Using mice that allow conditional deletion of Zeb2, we will study the function, phenotype, survival and differentiation of Zeb2-deficient CD8+ T cells during primary and secondary immune responses. 2) Elucidate the transcriptional network involved in the differentiation and survival of shorter-lived effector-memory CD8+ T cells. We will identify the targets of Zeb2 during T cell activation and explore the potential interplay between Zeb2 and other transcription factors in promoting the development of effector-memory CD8+ T cells. 3) Establish how Zeb2 expression impacts human CD8+ T cell effector and/or memory differentiation. We will characterize the CD8+ T cell subsets of Mowat-Wilson syndrome patients, who have mutations leading to Zeb2 heterozygosity, and study how loss or gain of Zeb2 expression influences the activation, function and differentiation of T cells from healthy human controls. In these studies we will define the role of the transcriptional repressor Zeb2 in immunity for the first time, allowing us to directly conclude if the same transcription factors control the generation of effector and memory T cell subsets in mice and humans. Ultimately, an understanding of the molecular pathways that underlie the generation and function of memory T cells will allow the ability to either promote or re-direct the formation of functional memory T cell subsets during an immune response, improving the strategic design of therapeutic and protective vaccines.)